This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic 08-ES-104, Identification of Alterations in Epigenetic Marks Related to Environmental Exposures. Environmental exposure to foreign chemicals with estrogenic activities is widespread and is proposed to impact adversely on human health. Exposure to these xenoestrogens and other endocrine-disrupting chemicals has been associated with a variety of developmental and reproductive abnormalities, with humans and other species being hypersensitive to endocrine-active compounds during critical periods of embryonic, fetal and early postnatal life. The overall goal of this project is to investigate the hypothesis that perinatal exposure to xenoestrogens induces epigenetic marks associated with permanent changes in expression of key genes controlling female reproductive tract development, which are, in turn, linked to the observed reproductive tract abnormalities and increased incidence of uterine cancer. It is proposed that each xenoestrogen has a unique epigenetic signature as a result of its unique activity as a selective estrogen receptor modulator. These hypotheses will be tested using in utero mouse models of exposure to the xenoestrogens diethylstilbestrol and bisphenol-A. Diethylstilbestrol is a potent xenoestrogen linked to major reproductive tract developmental abnormalities in mouse models and in exposed humans, while bisphenol-A is a weak xenoestrogen that induces more modest reproductive toxicities in the mouse;the consequences of human exposure to the latter chemical are not definitively established. Discovery of the epigenetic signatures that are common, as well as those that are unique, to each xenoestrogen will help elucidate the reproductive toxicology associated with each chemical. These studies will provide important new insight into the mechanisms through which endocrine-active environmental chemicals induce reproductive toxicities, and may, ultimately, lead to new strategies for detection and prevention of adverse effects in exposed individuals. The significance of the studies proposed is major, both in terms of the new scientific knowledge that is expected to result, and for the potential impact on the large number of individuals that are exposed to environmental xenoestrogens. The economic stimulatory impact is also expected to be major, advancing Recovery Act goals through the direct hiring of research staff to support the needs of this project and via the positive economic stimulus that will result from the expenditure of laboratory research supplies funds. PUBLIC HEALTH RELEVANCE: This project investigates the actions of environmental chemicals that exert reproductive toxicities, with special emphasis on environmental estrogens that induce female reproductive tract toxicities in humans and other exposed mammals. The studies that are proposed will provide important new insight into the mechanisms through which endocrine-active environmental chemicals induce reproductive toxicities, and may, ultimately, lead to new strategies for detection and prevention of adverse effects in exposed individuals.